Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Advances and Contributions
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Advances and Contributions
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Advances and Contributions
Background and rationale. After the introduction of insulin therapy in 1922, type 1 diabetes (T1D) was transformed from a uniformly fatal disease to a chronic
degenerative one (4). During the 19301960s, the development of chronic complications affecting the eyes,
kidneys, peripheral and autonomic nervous system, and
a substantially increased risk of cardiovascular disease
(CVD) were observed in patients who had survived .20
years with the disease (5). The origin of these newly discovered complications was debated vigorously, and theories to explain them abounded (4,6). The debate led to two
FIG. 1. Study time line of the DCCT/EDIC Study. RFA, research funding
announcement.
TABLE 1
Eligibility criteria of primary prevention and secondary intervention cohorts
Age (years)
Diabetes duration (years)
C-peptide (nmol/L)
Basal
Stimulated
Retinopathy
Nephropathy (albumin excretion rate)
Neuropathy
Blood pressure (mmHg)
Lipids (serum cholesterol)
Primary prevention
Secondary intervention
1339
15
1339
15
#0.2
#0.5
None
#0.2
#0.2*
$1 microaneurysm but , moderate
severe NPDR
,40 mg/24 h
#200 mg/24 h
No symptomatic neuropathy requiring therapy
,140 systolic and ,90 diastolic
,3 SD above for mean for sex and age
NPDR, nonproliferative diabetic retinopathy. *Same stimulated level as those of the primary prevention group if duration ,5 years.
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Cardiovascular. CVD is an important, although nonspecic, complication of T1D; however, the DCCT population was generally too young and too healthy, with
subjects with prior CVD or hypertension or dyslipidemia
excluded during screening, to observe enough major
CVD cases and events during the DCCT (24 events in 12
subjects) for reliable analysis (23). Nonetheless, there
was a tantalizing, albeit nonsignicant (P = 0.059), difference in CVD events between the INT (3 events in 3
subjects) and CONV (21 events in 9 subjects) treatment
groups.
b-Cell preservation. During the selection of the DCCT
cohort, patients with persistent, albeit low-level, insulin
secretion, measured as a stimulated C-peptide concentration .0.2 but #0.5 nmol/L 90 min after a mixed-meal
challenge, were allowed into the study if their diabetes
duration at baseline was ,5 years (Table 1). Three hundred and three subjects fullled this criterion, of whom 165
were randomly assigned to CONV and 138 to INT (24).
Although the C-peptide concentrations declined progressively during the rst 6 years of the DCCT, with only
a handful of subjects retaining measureable C-peptide
concentrations, INT slowed the rate of loss of C-peptide
responsiveness by ~50% (24). The clinical benets of persistent C-peptide secretion included signicantly lower
HbA1c levels with lower insulin doses, fewer hypoglycemic
episodes, and signicantly less retinopathy. The clinically
important effects of C-peptide preservation further emphasized the application of INT early in the course of diabetes and currently serve as the main rationale for b-cell
preservation studies.
Quality of life. A diabetes-specic quality of life (DQOL)
measure was developed to assess the effects of DCCT
interventions (25). It tested satisfaction, impact, diabetes
worry, and social/vocational worry. Approximately 20% of
participants in the INT and CONV treatment groups had
signicant decreases in their DQOL by DCCT closeout;
however, despite the rigors of INT and associated hypoglycemia, the difference in QOL between INT and CONV
groups was nonsignicant (26).
Neurocognitive function. Repeated severe hypoglycemic events, especially with coma or seizure, raised concern that INT might adversely affect long-term cognitive
ability. Conversely, a putative benet of INT regarding the
accelerated cognitive decline associated with diabetes
was postulated. At DCCT closeout, there were no substantive or signicant differences in cognitive function
between the treatment groups, despite the threefold increased frequency of severe hypoglycemia with INT (27).
Moreover, the cumulative number of severe hypoglycemic events had no inuence on cognitive test results,
which were within the range recorded for a large sample
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TABLE 2
Clinical characteristics of DCCT/EDIC participants at DCCT baseline, DCCT closeout, and EDIC year 18
DCCT baseline
(19831989) (N = 1,441)
INT
CONV
N
Medical history
Age (years)
Female (%)
Diabetes duration (years)
DCCT primary cohort (%)
Hypertension (%)||
Hyperlipidemia (%)**
Current cigarette smoking (%)
Medical treatment
Glucose management
Pump or multiple daily injections ($3) (%)
Glucose monitoring $4 times a day (%)
Use of antihypertensive medication (%)
Any
ACE inhibitor or ARB
Physical examination
BMI (kg/m2)
Obese (BMI $30 kg/m2) (%)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Mean arterial pressure (mmHg)
Laboratory values
HbA1c (%)
Plasma lipids (mg/dL)
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
Complications
Eye
Retinopathy levels (%)
No retinopathy (10/10)
MA Only (20/#20)
Mild NPDR (35/#35)
Moderate NPDR (43/,43 to 53/53)
Severe PDR or worse (53/,53 and above)
Renal
AER (%)
0 to ,30 mg/24 h
30 to ,300 mg/24 h
$300 mg/24 h or ESRD
eGFR (mL/min/1.73 m2)
Sustained eGFR ,60 mL/min/1.73 m2 (%)
Conrmed clinical neuropathy (%)
711
730
27.2 (7.1)
48.5
5.8 (4.2)
49.0
3.1
22.8
18.6
0
0
0
0
0
0
23.4
1.3
114.5
73.1
86.9
(2.7)
23.5
1.9
(11.3) 114.6
(8.2)
72.9
(8.2)
86.8
9.1 (1.6)
177.1
50.8
110.3
80.8
49.0
35.0
11.6
4.5
0
698
26.7 (7.1)
45.9
5.5 (4.1)
51.8
2.1
23.4
18.4
0
0
End of DCCT
(1993) (N = 1,422)*
INT
CONV
717
33.6 (7.0)
49.0
12.3 (4.9)
49.1
4.4
25.6
20.2
97.4
52.7
(2.9)
26.6
18.6
(11.4) 116.3
(8.7)
74.4
(8.6)
88.3
9.1 (1.6)
620
33.0 (7.0)
46.0
11.9 (4.8)
51.7
3.9
29.7
19.8
5.0
3.8
(4.2)
25.0 (3.1)
5.6
(11.7) 115.3 (12.0)
(8.8)
74.3 (8.8)
(8.9)
88.0 (8.9)
7.2 (0.9)
EDIC year 18
(20102012) (N = 1,284)*
INT
CONV
9.1 (1.3)
597
52.3 (6.9)
48.7
30.7 (5.0)
47.7
66.6
68.6
11.5
51.4 (6.9)
45.7
30.2 (4.9)
50.6
68.8
68.2
10.7
97.6
67.7
97.7
70.7
60.3
56.8
62.7
59.8
29.1
36.1
122.4
71.4
88.4
(5.7)
28.5
33.0
(15.4) 121.8
(9.0)
71.3
(9.8)
88.2
8.0 (1.0)
(5.1)
(15.1)
(8.8)
(9.6)
8.0 (1.0)
(32.8) 175.7 (33.6) 178.8 (31.2) 183.4 (36.6) 174.8 (35.4) 172.1 (36.4)
(12.3) 50.3 (12.3) 50.8 (12.8) 51.5 (12.9)
61.9 (19.4) 61.5 (17.7)
(28.7) 109.1 (29.4) 111.6 (27.2) 114.3 (31.4)
96.7 (29.2) 94.7 (29.5)
(43.3) 81.8 (51.3) 82.0 (51.6) 87.8 (54.0) 81.1 (50.6) 80.6 (71.5)
51.8
27.8
15.2
5.1
0.1
28.3
39.7
21.2
8.2
2.6
17.3
32.1
28.5
14.3
7.8
88.3
90.0
89.8
82.2
11.7
10.1
8.8
14.6
0
0
1.4
3.2
126.0 (13.9) 126.2 (14.6) 116.0 (13.0) 117.8 (13.7)
0
0
0.1
0.4
6.8
5.6
9.3
17.5
10.7
36.9
21.3
16.5
14.7
4.7
26.8
18.3
19.6
30.7
81.5
14.2
4.3
93.3 (18.1)
3.2
23.6
75.1
17.0
7.9
91.7 (20.1)
5.3
32.7
Data are means (SD) unless otherwise indicated. ARB, angiotensin II receptor blocker; eGFR, estimated glomerular ltration rate; ESRD, endstage renal disease; MA, microaneurysms; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. *Renal
measurements (AER or estimated glomerular ltration rate) were completed for 1,415 subjects at DCCT closeout and 1,217 subjects at
EDIC year 17 or 18 (1,194 with AER at year 17 or 18 and 1,187 with eGFR at year 18). For EDIC year 18, clinical characteristic values were
carried from measurements from the most recent visit if not measured at year 18. AER and lipid data were collected at year 17 or 18. P , 0.05
by the Wilcoxon rank sum test or the x2 test comparing conventional and intensive treatment. ||Hypertension was dened by a systolic blood
pressure $140 mmHg, diastolic blood pressure $90 mmHg, or use of antihypertension medications. **Hyperlipidemia was dened by an LDL
cholesterol level $130 mg/dL (3.4 mmol/L) or the use of lipid-lowering agents. P , 0.01 by the Wilcoxon rank sum test or the x2 test
comparing conventional and intensive treatment (comparing the distribution of levels within retinopathy and within nephropathy). Medication data were not collected during the DCCT. ACE inhibitors were prohibited during the DCCT. At EDIC year 1, ACE inhibitor use was 5.6%
in INT and 6.9% in CONV. Angiotensin II receptor blockers were not available until later during the EDIC. Antihypertensive use was 8.7% in
INT and 10.1% in CONV. End of DCCT HbA1c values are time-averaged mean HbA1c throughout the DCCT; EDIC year 17/18 HbA1c values are
time-averaged mean EDIC HbA1c. Mean (SD) HbA1c levels time averaged through the DCCT/EDIC were 7.8% (0.9) and 8.3% (1.0) among
participants assigned to INT and CONV, respectively.
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TABLE 3
Retention of DCCT/EDIC cohort over time
DCCT
N
Percent of
original
cohort
Percent of
surviving
cohort
EDIC
Baseline
(19831989)
Study
end
(1993)
Baseline
(1994)
Year 11
(2005)
Year 19
(2012)
1,441
1,422
1,394
1,340
1,284
100
99
96
93
89
99
97
96
95
of healthy persons without diabetes. For example, subjects with more than one episode of coma or seizure per
year had no signicant differences in the cognitive tests
compared with subjects with one or fewer episodes per
year (27). The testing assessed eight domains of neurocognitive function. INT did have a modest, signicant (P =
0.004) benecial impact on motor speed compared with
CONV. Thus, at least within the limited exposure period
of DCCT, INT and associated hypoglycemia did not impair cognitive function and may have had a limited benet. Similar ndings were noted in the adolescent DCCT
population.
ADVERSE EFFECTS OF INTENSIVE TREATMENT
Rationale and design. At the end of the DCCT, the salutary effects of INT on early-stage microvascular complications had been demonstrated; however, the relatively
brief duration of diabetes and presence at baseline of no or
only minimal-to-moderate complications meant that the
differential effects of INT on more advanced complications, including cardiovascular disease, could not be
studied. The major goal of EDIC was to follow the DCCT
cohort for the time required to determine whether the
original DCCT therapies would have a longer-term effect
on more advanced stages of diabetes microvascular complications and their clinical sequelae and on CVD (2).
At the end of the DCCT, as a consequence of the salutary
effects of INT versus CONV, all of the CONV group participants were trained in INT by DCCT staff, although
hospitalization to implement such therapy was not performed. In addition, since EDIC was envisioned as observational in nature, the diabetes care of all participants was
subsequently transferred to their own care providers, with
;50% initially maintaining clinical care at the institution
that housed their DCCT clinic. EDIC evaluations were
performed annually with methodologies that were largely
identical as in DCCT, and extensive efforts were made to
FIG. 2. Median HbA1c from DCCT through EDIC year 19. HbA1c was measured quarterly in CONV (dashed line) and INT (solid line) during DCCT
and annually during EDIC.
3980
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FIG. 4. A: Relationship of current updated mean HbA1c levels with three-step progression of retinopathy. B: Relationship of current HbA1c levels
measured every 3 months during DCCT with occurrence of severe hypoglycemia, dened as episodes of hypoglycemia requiring assistance for
treatment. PYR, patient-years.
during EDIC, the average frequency of severe hypoglycemia is now similar (39.7 and 35.1/100 patient-years,
respectively).
The comprehensive evaluation of eight domains of
cognitive function during DCCT did not reveal any pernicious effects of INT, or of the accompanying increased
occurrence of hypoglycemia, on any domain of cognitive
function (27). Repeat testing was performed at EDIC year
12, ~18 years after the initiation of DCCT therapy, to determine whether prior hypoglycemia might cause even
longer-term adverse effects (50). There were no signicant
differences in any of the eight domains between the original treatment groups or between those who had experienced frequent severe hypoglycemia episodes and those
who had not (50). Similar ndings were noted in the subcohort that entered the DCCT as adolescents (51).
Mechanisms and risk factors for microvascular disease.
While a dominant role for hyperglycemia in the development and progression of complications can no longer be
questioned, the mechanistic connection(s) between hyperglycemia and complications remains to be elucidated.
Moreover, metabolic memory needs to be explained. Genetics and other DCCT/EDIC ancillary studies have offered possible explanations for these related mechanistic
issues.
The DCCT conducted a family study including 217
DCCT probands and 241 rst-degree family members with
either type 1 or type 2 diabetes in order to explore
3982
potential genetic effects on the risk for developing complications (52). The study demonstrated familial clustering
of complications, including retinopathy and nephropathy.
Subsequent studies have examined DNA samples collected
from the entire DCCT cohort, using candidate gene and
genome-wide association scanning to identify genetic risk
factors for complications. These studies have identied or
conrmed several loci that appear to confer risk for the
development of retinopathy (53), nephropathy (54,55), and
erectile dysfunction (56).
As with the glycation of hemoglobin in circulating
erythrocytes, tissue proteins also undergo glycation. After
nonenzymatic glycation of amino groups in collagen and
subsequent reactions and rearrangements, advanced glycation end products (AGEs), such as pentosidine, glucosepane, and carboxymethyllysine, are produced. These act
to cross-link proteins, potentially altering their structure
and function. Human collagen has a very long half-life, e.g.,
15 years for dermal collagen, and is a major component of
basement membrane that is altered in diabetic tissues.
Three DCCT/EDIC observations support a role for AGEs
in the pathogenesis of complications. In a cross-sectional
study of 216 DCCT participants who had skin punch biopsies near the time of DCCT closeout, a panel of AGEs in
collagen and alteration of collagen solubility were correlated with the presence of retinopathy, nephropathy, and
neuropathy independent of HbA1c (57). The AGEs proved
to be predictive risk factors for the development and
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Improved insulin formulations and regimens, and laboratory and technological advances, have all contributed to
adoption of intensive diabetes management since the end
of the DCCT in 1993. At the time that the DCCT results
were announced, community estimates indicated that
~21% of individuals with T1D were using a single type of
insulin, 8% of individuals with T1D were using a single
daily injection, 13% were using MDI strategies, and ,1%
were using CSII (59,60). For those using more than one
injection, a twice-daily split mix (regular/NPH) was the
most commonly used regimen (61). Although urine glucose
monitoring was being phased out in the late 1980s, as more
convenient, accurate, and less costly SMBG devices were
introduced, only ;45% of individuals with T1D reported
performing SMBG at least once daily (60,61). In 1989, 7% of
a sample of individuals with T1D reported having an HbA1c
test within the past 6 months, 57% had never heard of the
test, and the mean HbA1c in the community was reported
as .10% (60,61). Prior to the development of the ADA
Standards of Medical Care in 1989, no evidence-based
standards for medical care of diabetes existed. The ADA
standards before the end of the DCCT recommended glucose monitoring without specifying urine or blood or the
frequency of testing (62). Assessment of glycemic control
using HbA1c was not well established, and laboratory
measurements of this parameter were not standardized.
The results of the DCCT delivered the simple message
that glucose control matters. As a result, individuals with
diabetes and the health care community were challenged
to reevaluate the prevailing views and diabetes care
practices. The DCCT endorsed intensive insulin therapy
using three or more daily insulin injections or CSII, frequent daily SMBG, and quarterly assessment of HbA1c,
with the overall goal being to achieve glycemic control as
close to the nondiabetic range as safely possible for people
with T1D. Multidisciplinary team care as practiced in the
DCCT (63,64), use of SMBG results to make daily proactive and reactive dose adjustments, and frequent communication between the patient and the patients health
care team were advocated and quickly incorporated into
consensus recommendations along with DCCT-established
glycemic targets (20). Flexible nutrition management and
compensatory adjustments were emphasized to promote
adoption of this more rigorous treatment regimen into
daily life, with emphasis changed from adjusting meals
and lifestyle to match insulin to the manipulation of insulin to match lifestyle. The National Glycohemoglobin Standardization Program, established by DCCT investigators,
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